Brain VDR Regulate Glucose Balance

Brain VDR 调节血糖平衡

基本信息

  • 批准号:
    10444524
  • 负责人:
  • 金额:
    $ 48.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-04-05 至 2027-03-31
  • 项目状态:
    未结题

项目摘要

Our lack of understanding regarding how vitamin D regulates glucose prevents its use as an effective diabetes therapy. We have shown that vitamin D can act in the brain to lower glucose levels and that loss of vitamin D receptors (VDR) within the paraventricular hypothalamus (PVH) of the brain are critical for normal glucose levels in obese, but not lean, animals. However, the neurocircuitry/function of VDRPVH neurons, the role of the PVH VDR responding to dietary vitamin D, and mechanisms underlying effects in obese but not lean states are unknown. This raises basic questions regarding how vitamin D receptors mediate glucose balance. We have generated a genetic mouse model with Cre recombinase expression in VDR positive cells (VDRCre). This provides an excellent model to determine the function, necessity, and downstream neuronal targets of VDRPVH neurons. Additionally, utilizing other genetic tools, we can determine if VDR within the PVH are necessary for changes in blood glucose by dietary vitamin D. Last, we can utilize these tools to determine the mechanisms underlying weight-specific effects of vitamin D in the brain on glucose regulation. The objective of this grant is to determine the mechanisms of vitamin D in the brain on glucose balance. We hypothesize that VDR regulate glucose levels through distinct neuronal circuits and through genomic effects in PVH neurons. The central hypothesis will be tested by three specific aims: 1) identifying neuronal mechanisms for PVH VDR positive neurons; 2) determining if PVH VDR are required or sufficient for dietary-vitamin D changes in glucose homeostasis; and 3) establishing mechanisms for the glucose-protective effect of vitamin D in an obese model. In Aim 1, we will use chemogenetics, single-cell genomics, and immunohistochemistry to determine the function, identity, and circuitry of VDRPVH neurons. In Aim 2, we will use different dietary manipulations of vitamin D to test if PVH VDR are necessary for high-vitamin D induced glucose improvements. Additionally, we will determine if central administration of active vitamin D can overcome deleterious effects of low dietary vitamin D on glucose balance. In Aim 3, we will determine how obesity alters the transcriptomic and neuronal activation response to active vitamin D (1,25D3). Additionally, we will determine if there are differences in VDR expression or VDR+ neuronal number in obese vs. lean states. The research proposed is innovative, because it investigates the function of a novel neuronal population (VDRPVH) on glucose tolerance, using a novel mouse model. The proposed research is significant because it is expected to identify new paradigms to understand vitamin D action, as well as possibly identifying a novel circuit in the PVH with critical glucose-regulating properties. Results from this research may ultimately explain some of the variance in clinical trials utilizing vitamin D as a therapy and provide critical information to advance the use of vitamin D as a therapeutic agent. Altogether, I envision that the completion of this proposal will move this research towards the long-term goal of understanding how to utilize vitamin D as an effective therapy for type 2 diabetes.
我们对维生素D如何调节葡萄糖缺乏了解,这阻碍了它作为有效的糖尿病药物的使用

项目成果

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Stephanie Renee Sisley其他文献

Stephanie Renee Sisley的其他文献

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{{ truncateString('Stephanie Renee Sisley', 18)}}的其他基金

Brain VDR Regulate Glucose Balance
Brain VDR 调节血糖平衡
  • 批准号:
    10602497
  • 财政年份:
    2022
  • 资助金额:
    $ 48.28万
  • 项目类别:
Mechanisms of CNS Vitamin D Receptor in Weight Regulation
CNS维生素D受体体重调节机制
  • 批准号:
    9180244
  • 财政年份:
    2016
  • 资助金额:
    $ 48.28万
  • 项目类别:
CNS NFkappaB Regulation of Glucose Homeostasis
CNS NFkappaB 血糖稳态调节
  • 批准号:
    8201854
  • 财政年份:
    2011
  • 资助金额:
    $ 48.28万
  • 项目类别:
CNS NFkappaB Regulation of Glucose Homeostasis
CNS NFkappaB 血糖稳态调节
  • 批准号:
    8411657
  • 财政年份:
    2011
  • 资助金额:
    $ 48.28万
  • 项目类别:

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